Calcium plays essential roles in various cell processes including cell metabolism, muscle contraction, molecular secretion and mitogenesis. Calcium is mostly stored in endoplasmic reticulum (ER) in non-muscle cells, and in the sarcoplasmic reticulum (SR) in muscle cells. The regulation of calcium involves a family of homologous, calcium-binding proteins such as calbindins, troponin C, calmodulin, and S-100 proteins. These proteins contain a common structural motif, the EF-hand motif, which consists of two .alpha.-helices separated by a loop of 12 to 13 amino acid residues.
Some proteins identified in the lumen of ER, such as BiP, protein disulfide isomerase, calreticulin, and endoplasmin, are also involved in the regulation of calcium. These proteins do not have the EF-hand motif; they are retained in the lumen by a membrane-bound receptor. The receptor retrieves the luminal ER proteins from Golgi apparatus to the ER lumen by recognizing their carboxy-terminal tetrapeptide, Lys-Asp-Glu-Leu (KDEL) or His-Asp-Glu-Leu (HDEL). An exception to these ER proteins is reticulocalbin, a lumenal protein of the ER which possesses both the EF-hand motif and the ER-retention signal, HDEL (Ozawa, M. and Muramatsu, T. (1993) J. Biol. Chem. 268:699-705; Ozawa, M. (1995) J. Biochem. 117: 1113-1119). In fact, the mouse reticulocalbin, a 44 kDa protein, has six repeats of the EF-hand motif. The human reticulocalbin, which shares 95% identity with its mouse homolog, was cloned using the mouse gene (Ozawa, supra).
The discovery of a novel calcium-binding protein similar to reticulocalbin and the polynucleotide which encodes it satisfies a need in the art by providing new compositions which are useful in diagnosing, preventing, and treating disorders associated with cell proliferation.